NCLs and ER: A stressful relationship.

The Neuronal Ceroid Lipofuscinoses (NCLs, Batten disease) are a group of inherited neurodegenerative disorders with variable age of onset, characterized by the lysosomal accumulation of autofluorescent ceroid lipopigments. The endoplasmic reticulum (ER) is a critical organelle for normal cell function. Alteration of ER homeostasis leads to accumulation of misfolded protein in the ER and to activation of the unfolded protein response. ER stress and the UPR have recently been linked to the NCLs. In this review, we will discuss the evidence for UPR activation in the NCLs, and address its connection to disease pathogenesis. Further understanding of ER-stress response involvement in the NCLs may encourage development of novel therapeutical agents targeting these pathogenic pathways

Quantifier-Free Interpolation of a Theory of Arrays

The use of interpolants in model checking is becoming an enabling technology to allow fast and robust verification of hardware and software. The application of encodings based on the theory of arrays, however, is limited by the impossibility of deriving quantifier- free interpolants in general. In this paper, we show that it is possible to obtain quantifier-free interpolants for a Skolemized version of the extensional theory of arrays. We prove this in two ways: (1) non-constructively, by using the model theoretic notion of amalgamation, which is known to be equivalent to admit quantifier-free interpolation for universal theories; and (2) constructively, by designing an interpolating procedure, based on solving equations between array updates. (Interestingly, rewriting techniques are used in the key steps of the solver and its proof of correctness.) To the best of our knowledge, this is the first successful attempt of computing quantifier- free interpolants for a variant of the theory of arrays with extensionality

New results on rewrite-based satisfiability procedures

Program analysis and verification require decision procedures to reason on theories of data structures. Many problems can be reduced to the satisfiability of sets of ground literals in theory T. If a sound and complete inference system for first-order logic is guaranteed to terminate on T-satisfiability problems, any theorem-proving strategy with that system and a fair search plan is a T-satisfiability procedure. We prove termination of a rewrite-based first-order engine on the theories of records, integer offsets, integer offsets modulo and lists. We give a modularity theorem stating sufficient conditions for termination on a combinations of theories, given termination on each. The above theories, as well as others, satisfy these conditions. We introduce several sets of benchmarks on these theories and their combinations, including both parametric synthetic benchmarks to test scalability, and real-world problems to test performances on huge sets of literals. We compare the rewrite-based theorem prover E with the validity checkers CVC and CVC Lite. Contrary to the folklore that a general-purpose prover cannot compete with reasoners with built-in theories, the experiments are overall favorable to the theorem prover, showing that not only the rewriting approach is elegant and conceptually simple, but has important practical implications.Comment: To appear in the ACM Transactions on Computational Logic, 49 page

Retraction Note: Cognitive deficits in multiple sclerosis: a review of functional MRI studies

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Diffusion MRI Findings in Encephalopathy Induced by Immunosuppressive Therapy after Liver Transplantation

Neurological complications are common after liver transplantation, as they affect up to one-third of the transplanted patients and are associated with significant morbidity. The introduction of calcineurin inhibitors, cyclosporine A and tacrolimus, in immunosuppressive regimens significantly improved the outcome of solid-organ transplantation even though immunosuppression-associated neurotoxicity remains a significant complication, particularly occurring in about 25% of cases after liver transplantation. The immunosuppressant cyclosporine A and tacrolimus have been associated with the occurrence of major neurological complications, diffuse encephalopathy being the most common. The biochemical and pathogenetic basis of calcineurin inhibitors-induced neurotoxicity are still unclear although several mechanisms have been suggested. Early recognition of symptoms could help reduce neurotoxic event. The aim of the study was to evaluate cerebral changes through MRI, in particular with diffusion-weighted images (DWI) and apparent diffusion coefficient (ADC) maps, in two patients undergoing liver transplantation after immunosuppressive therapy. We describe two patients in which clinical pictures, presenting as a severe neurological condition, early after orthotopic liver transplantation during immunosuppression therapy, showed a different evolution in keeping with evidence of focal-multifocal lesions at DWI and ADC maps. At clinical onset, DWI showed hyperintensity of the temporo-parieto-occipital cortex with normal ADC values in the patient with following good clinical recovery and decreased values in the other one; in the latter case, MRI abnormalities were still present after ten days, until the patient's exitus. The changes in DWI with normal ADC may be linked to brain edema with a predominant vasogenic component and therefore reversible, while the reduction in ADC is due to cytotoxic edema and linked to more severe, nonreversible, clinical picture. Brain MRI and particularly DWI and ADC maps provide not only a good and early representation of neurological complications during immunosuppressant therapy but can also provide a useful prognostic tool on clinical outcome of the patient

Global network analysis in Schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile CLN3 disease

Juvenile CLN3 disease is a recessively inherited paediatric neurodegenerative disorder, with most patients homozygous for a 1-kb intragenic deletion in CLN3. The btn1 gene is the Schizosaccharomyces pombe orthologue of CLN3. Here, we have extended the use of synthetic genetic array (SGA) analyses to delineate functional signatures for two different disease-causing mutations in addition to complete deletion of btn1. We show that genetic-interaction signatures can differ for mutations in the same gene, which helps to dissect their distinct functional effects. The mutation equivalent to the minor transcript arising from the 1-kb deletion (btn1102–208del) shows a distinct interaction pattern. Taken together, our results imply that the minor 1-kb deletion transcript has three consequences for CLN3: to both lose and retain some inherent functions and to acquire abnormal characteristics. This has particular implications for the therapeutic development of juvenile CLN3 disease. In addition, this proof of concept could be applied to conserved genes for other mendelian disorders or any gene of interest, aiding in the dissection of their functional domains, unpacking the global consequences of disease pathogenesis, and clarifying genotype–phenotype correlations. In doing so, this detail will enhance the goals of personalised medicine to improve treatment outcomes and reduce adverse events

Author Correction: Global network analysis in Schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile CLN3 disease

The original version of this Article contained errors in Figure 1c, where data points in the bar graph plot appeared incorrectly in green colour. As a results, the Figure legend, “General overview of SGA analysis of btn1 mutants versus ade6 control. (A) Representative images of the SGA plates for control (ade6) and query mutants (btn1Δ, btn1D363G, btn1102–208del), with empty control quadrants shown for ade6 (yellow boxes). (B) Exclusion of small colonies for ade6 control across batches as they represent high variability therefore reducing noise. (C) Principle component biplot of the variance within the SGA data for ade6 control (yellow) and query-mutants btn1Δ (blue), btn1D363G (green), btn1102–208del (red), with experimental batch indicated. (D) Cluster analysis for each strain and all the genes with their normalised colony size difference against ade6 control with batch effects removed. Interactions are coloured in blue for negative interactions ( 0.5). (E) Gene linkage of normalised fitness score for ade6 control and query mutants btn1Δ, btn1D363G, btn1102–208del from one experiment. Vertical dashed line represents ade6 or btn1 gene location, red points represent interaction scores excluded from data since less than 500 kb/500,000 bps from query gene location.” now reads: “General overview of SGA analysis of btn1 mutants versus ade6 control. (A) Representative images of the SGA plates for control (ade6) and query mutants (btn1Δ, btn1D363G, btn1102–208del), with empty control quadrants shown for ade6 (yellow boxes). (B) Exclusion of small colonies for ade6 control across batches as they represent high variability therefore reducing noise. (C) Principle component biplot of the variance within the SGA data for ade6 control (yellow) and query-mutants btn1Δ (blue), btn1D363G (orange), btn1102–208del (red), with experimental batch indicated. (D) Cluster analysis for each strain and all the genes with their normalised colony size difference against ade6 control with batch effects removed. Interactions are coloured in blue for negative interactions ( 0.5). (E) Gene linkage of normalised fitness score for ade6 control and query mutants btn1Δ, btn1D363G, btn1102–208del from one experiment. Vertical dashed line represents ade6 or btn1 gene location, red points represent interaction scores excluded from data since less than 500 kb/500,000 bps from query gene location